The present invention relates to a device and method for non-invasively monitoring respiratory diseases. More particularly, the present invention relates to a device and method for determining the pH or NH4+ concentrations of condensed breath exhalate to detect, diagnose and treat asthma.
Asthma is a chronic inflammatory disorder of the airways affecting the world population in epidemic proportions. Indeed, approximately five percent of the world population are affected. This means that over 15 million Americans, and hundreds of millions of others worldwide, are susceptible. In the United States, over 400,000 hospitalizations for asthma were required during 1994, and over 1.9 million asthma related emergency room visits were made during 1995. Over 5,000 asthma related deaths occur in the United States each year. See http://www.asthmainamerica.com (Oct. 15, 1999).
In susceptible individuals, asthma causes recurrent episodes of coughing, wheezing, chest tightness, and difficult breathing. Inflammation makes airways sensitive to stimuli such as allergens, chemical irritants, tobacco smoke, cold air and exercise. When exposed to such stimuli, airways may become swollen, constricted, filled with mucus, and hyper responsive to stimuli.
There currently is no cure for asthma, but two types of treatments that suppress asthma symptoms and prevent attacks are currently used by many asthma sufferers. One of these types of treatments employs quick-relief medications, such as inhaled bronchodilator therapy, which works quickly to suppress symptoms by relaxing airway smooth muscle. The other of these types of treatments employs long-term preventive medications, such as inhaled, oral, or intramuscular corticosteroids, and leukotriene antagonists, which can prevent the onset of symptoms and attacks by controlling the underlying inflammation, thereby keeping persistent asthma under control. Unfortunately, many of the preventive medications have undesirable side effects, such as serious as growth limitation in children, osteoporosis, weight gain, and cataracts. As a result, the failure to properly identify the amount of inflammation in the airways, and therefore the appropriate treatment for a subject""s asthmatic condition, may significantly adversely impact the subject""s health. To date, however, there is no generally accepted manner of readily determining whether a given patient requires treatment, let alone what specific type of treatment should be used.
Conventionally, asthma is diagnosed by examining a number of indicators and qualitatively assessing the observed results. For example, a clinical diagnosis of asthma is often prompted by a combination of symptoms such as episodic breathlessness, wheezing, chest tightness, and coughing. However, these symptoms often occur only nocturnally and therefore are difficult for a doctor to monitor or measure. In addition, recently manifested symptoms alone are neither diagnostic indicators for asthma nor true measures of severity, so doctors must often evaluate a patient""s health over long time periods before a diagnosis of asthma may be made with reasonable confidence. Because of the difficulty inherent in diagnosing asthma, doctors must use a patient""s response to asthma treatments as a diagnostic tool. For example, the fact that bronchodilator treatment results in the relief of symptoms generally associated with asthma could indicate the presence of asthma. Disadvantageously, such diagnosis methods may result in the unnecessary application of asthma medications which have undesirable side effects. Accordingly, it would be desirable to have a device and method for readily diagnosing asthma before engaging in a course of treatment.
After a physician has covered the difficult ground of determining whether a person suffers from asthma, the physician must go through another process to determine the degree of severity of the asthma in order to prescribe an appropriate course of treatment. As with the diagnosis of asthma generally, there currently is no simple or noninvasive way to measure the degree of inflammation. There also is no objective method for determining when a course of treatment for airway inflammation can be discontinued. Accordingly, it would be desirable to have a device and method for simply, non-invasively and accurately determining the degree or severity of an asthmatic condition, and to what degree, if at all, a chosen course of treatment will be, or has been, effective.
In the past, few devices and methods for diagnosing asthma have been proposed, and those that have been proposed have not met with success. U.S. Pat. No. 5,922,610 to Alving, et al., issued Jul. 13, 1999, discloses a system and method for diagnosing inflammatory respiratory disorders related to abnormal nitric oxide (NO) levels in exhaled breathing air. The approach of the ""610 patent includes a mask into which a subject may breathe, filters for removing substances present in the exhaled air that may interfere with NO measurement, and an instrument which receives the uncondensed exhaled air and uses a chemiluminescence technique to measure the NO level of the exhalate. The approach of the ""610 patent therefore is very different from that of the present invention, which is drawn to diagnosing and treating respiratory diseases such as asthma by monitoring the acidity or ammonium concentrations of condensed exhalate.
Other devices and methods have been proposed which collect a breath sample for diagnostic purposes, but like the ""610 patent, none of these proposals teach or suggest testing a breath sample for acidity or ammonium concentrations to diagnose asthma or other respiratory diseases. For example, European Patent No. 0759169, published Nov. 23, 1995 (published with English translation of claims only), discloses a process and device for collecting expired breath content, which may later be evaluated to determine the condition and metabolic performance of organs such as the lungs and the respiratory system. Among other significant differences between the present invention and the approach of the ""169 patent, the latter does not appear to contemplate any specific respiratory disorders, such as asthma, in connection with which the disclosed device and process may be useful, nor does it appear to teach or suggest testing condensed breath exhalate for acidity or ammonium concentrations as an indicator of any respiratory disease. In addition, the ""169 patent does not appear to contemplate incorporating a means for testing a condensate in the breath collection device itself, during or immediately following breath condensate collection. Similarly, U.S. Pat. No. 5,081,871 to Glaser, issued Jan. 21, 1992, discloses an apparatus and method for collecting human exhaled breath for later analysis to determine whether the sample contains harmful substances such as volatile solvents, volatile compounds, endogenous compounds, volatile endogenously produced or used compounds, toxic chemicals, organic solvents, and natural air gasses. The ""871 patent does not relate to the collection and testing of a breath condensate, nor does it teach or suggest testing exhalate for acidityor ammonium concentrations to diagnose respiratory diseases. In addition, the device and method of the ""871 patent are substantially different from those of the present invention.
The present invention includes a method and device for monitoring a respiratory disease such as asthma in a subject. The method generally includes the steps of collecting condensate from a subject""s breath, testing the condensate to determine its acidity level or ammonium concentration, and evaluating the acidity level or ammonium concentration to determine the presence, absence or status of a respiratory disease in the subject. The method may also include, prior to the testing step, standardizing the volatile substances that may be present within the condensate. This may be done by a gas standardizing step or a degassing step. The gas standardizing step may include, for example, introducing atmospheric air to said condensate to standardize the amount of carbon dioxide in solution. The degassing step may include, for example, introducing an inert gas such as argon or helium to said condensate to remove acidifying carbon dioxide. It is contemplated that many respiratory diseases in humans or other vertebrates may be amenable to monitoring in accordance with the present method, including, for example, inflammatory respiratory diseases such as bronchiolitis, cystic fibrosis, smoking induced diseases, tuberculosis and occupational lung diseases. The method is believed to be particularly applicable to diagnosing and treating asthma.
The step of collecting condensate from a subject""s breath may include condensing breath that has been exhaled through the subject""s mouth, nose, or both. This step may further entail introducing the subject""s breath into a condensation apparatus which is capable of condensing the breath, and moving the condensate into a collection apparatus by force of gravity or by mechanical means, such as a pump. Once a breath sample has been received by the condensation apparatus, and preferably after at least a small sample of condensate has been produced by the condensation apparatus, the breath sample may be recirculated through the condensation apparatus until the condensation apparatus has produced a volume of condensate sufficient for the desired testing. In another aspect of the method of the present invention, the collecting step may include, before introducing a breath sample into the condensation apparatus, cooling the condensation apparatus (or one or more parts thereof) in a home freezer or other type of device to cool the condensation apparatus to a temperature lower than that of the condensate to be tested. The temperature to which the condensation apparatus is cooled, depending upon the material limitations of the apparatus, preferably is at least as low as 0xc2x0 C., and more preferably still at least as low as xe2x88x9240xc2x0 C. It will be appreciated, however, that the method of the present invention will operate at both higher and lower temperatures.
The step of testing the condensate may include using means for testing the condensate to determine said acidity level or ammonium level. Such means may include, among other things, an electronic or other type of monitor, or a solid, liquid or gaseous reagent introduced to the condensate directly or indirectly. Commonly available reagents include colorimetric pH reagents such as phenylphthalein, bromthymol blue or methyl red. Preferably, the testing step is performed within the collection apparatus using one or more of such methods, or other appropriate methods, eliminating the need to transport the condensate for testing elsewhere.
The step of evaluating said acidity level or ammonium concentration to determine the presence, absence or status of a respiratory disease in the subject may include, for example, evaluating the acidity level or ammonium concentration to diagnose, determine the severity of, determine a course of treatment for, determine the propriety of altering or discontinuing a course of treatment for, or predicting an impending exacerbation of a respiratory disease in a subject.
The device of the present invention, which may be used in performing the method of the present invention, generally includes a mouthpiece apparatus configured to receive breath from a subject, a condensation apparatus configured for operative connection to the mouthpiece apparatus and to condense the subject""s breath and produce a condensate, and a collection apparatus configured for operative connection to said condensation apparatus and having a collection chamber containing means for testing the condensate to determine its chemical properties. The device may also incorporate or be used in conjunction with an apparatus to standardize volatile substances within the condensate. The device therefore makes it possible to receive, condense, standardize and evaluate a breath sample from a subject in a single device in order to determine the presence, absence or status of a respiratory disease in the subject. Preferably, each of the mouthpiece apparatus, condensation apparatus, collection apparatus and collection chamber are separable from each other. More preferably still, the collection chamber is removable and disposable such that, once condensate has been collected therein, the chamber may be shipped to a testing facility. A conventional glass or plastic test tube, for example, would be suitable for many applications as such a disposable collection chamber. The condensation apparatus may include removable insulation, such that the insulation may be removed and the condensation apparatus placed in a home freezer or other cooling device prior to use.
The mouthpiece apparatus preferably includes a mouthpiece, which may be formed so that a subject may comfortably exhale from the user""s mouth and/or nose into the mouthpiece apparatus. The mouthpiece apparatus preferably also includes a first one-way valve configured to permit air to be drawn into the mouthpiece apparatus by a subject, and a second one-way valve configured to permit air to pass from the mouthpiece to a distal end of the mouthpiece apparatus. A particle or other type of filter may be positioned in the mouthpiece apparatus between the mouthpiece and the distal end of the mouthpiece apparatus.
The condensation apparatus of the device of the present invention preferably comprises an inner tube surrounded by an insulator. In one aspect of the invention, the inner tube has an outer surface, and the condensation apparatus further comprises an outer tube disposed between the inner tube and the insulator. In such a configuration, the inner surface of the outer tube and the outer surface of the inner tube preferably define a heat transfer chamber in which a solid, liquid or gas cooling material may be disposed to help cool or insulate the inner tube through which breath exhalate is to pass.
The collection apparatus may have a connector portion configured to connect the condensation apparatus to the collection chamber. The collection chamber preferably includes a measuring gradient, which may be configured for use as a quick reference to determine the volume of condensate that has been collected in the collection chamber during use of the device. The collection chamber also preferably contains means for testing the condensate to determine the chemical properties of the condensate. As described previously in connection with the method of the present invention, such means may include, among other things, an electronic or other type of monitor, or a solid, liquid or gaseous reagent introduced to the condensate directly or indirectly. For example, the collection chamber may have a reagent chamber therein containing one or more reagents. It could be configured so that condensate collects in the collection chamber, eventually coming into contact with the reagent in the reagent chamber, or so that as condensate is produced, it enters the reagent chamber within the collection chamber. Alternatively, the means for testing said condensate may comprise a retainer configured to hold a material, such as cloth or paper, in which one or more reagents are embedded or otherwise contained. In one aspect of the device of the present invention in which it is configured for determining the acidity level of a subject""s condensate, the reagent may be any pH reagent, including colorimeiric pH reagents such as phenylphthalein, bromthymol blue or methyl red. The means for testing may also include an electrode of an electronic monitor, which may optionally be configured to connect to the collection chamber or another part of the device by snaps, screw threads or other attachment means.
The apparatus for standardizing volatile substances within the condensate may comprise a degassing apparatus or a gas standardizing apparatus. The degassing apparatus may include a manual or automatic pump, or a compressed gas container or other apparatus, for drawing or forcing an inert gas through the condensate before or during the measurement of the acidity level, ammonium concentration, or other characteristics of the condensate. The gas standardizing apparatus also may include a pump or compressed gas container or other apparatus for passing atmospheric air through the condensate in a similar manner.